Abstract 480: Enhancing chemotherapy response by telotristat ethyl, an inhibitor of tryptophan hydroxylase involved in serotonin synthesis, in cholangiocarcinoma
Authors: Lily Darman, Margaret A. Schwarz, Roderich Schwarz, Niranjan Awasthi
Journal: Cancer Research (2023)

Abstract Objective: Cholangiocarcinoma (CCA) is a highly aggressive biliary tract cancer (BTC). CCAs are divided into three subtypes: intrahepatic (iCCA, 10-20%), perihilar (pCCA, 50-60%) or distal (dCCA, 20-30%). CCA has a very poor prognosis with a 5-year survival rate of 5-15%. The majority of CCA patients (~80%) present with unresectable disease where gemcitabine plus cisplatin (GemCis) is the standard treatment with a median survival of 14 months. Nanoparticle albumin-bound (nab) paclitaxel (NPT) is an approved treatment for breast cancer, NSCLC and pancreatic cancer that is under clinical investigation for several solid tumors including CCA. Increased accumulation and secretion of serotonin have been reported to support its oncogenic activity in CCA. Telotristat ethyl (TE) is an inhibitor of tryptophan hydroxylase 1 (TPH1) that mediates peripheral serotonin synthesis. We investigated the therapeutic efficacy of TE in combination with standard chemotherapies in preclinical models of CCA. Methods: Tumor growth studies were performed in subcutaneous cell-derived xenografts (CDX) using human CCLP-1 cells (iCCA), TFK-1 cells (dCCA), SNU-1196 cells (pCCA) in NOD/SCID mice, and in patient-derived xenografts (PDX) in NSG mice. Animal survival studies were performed in peritoneal dissemination xenografts in NOD/SCID mice using iCCA CCLP-1 cells. Intratumoral proliferation and serotonin levels were determined by immunohistochemistry (IHC). Results: In peritoneal dissemination xenografts, animal survival was markedly enhanced by NPT (60%), while TE (11%) or GemCis (9%) had a marginal effect. The combination of TE with GemCis (26%) or NPT (68%) exhibited a further increase in animal survival. In iCCA xenografts, tumor growth inhibition by TE was 53%, and NPT (69%) caused greater inhibition than GemCis (53%). In dCCA xenografts, tumor growth inhibition by TE was 51%, and NPT (56%) was more effective than GemCis (37%). In pCCA xenografts, tumor growth reduction by TE, NPT and GemCis was 41%, 67% and 58%. In all three cell-derived xenografts, TE combination with chemotherapy demonstrated an improved tumor growth inhibition effect (range: 67-90%). In PDX studies, TE markedly inhibited tumor growth (range: 40-73%), and GemCis caused a greater reduction (range: 80-86%) than NPT (57-76%). Again, an additive effect was observed with the combination of TE and chemotherapy. In all CDX and PDX subcutaneous tumors, reduction in tumor cell proliferation, measured by Ki67 staining, corresponded with tumor growth inhibition data. Further, decreased levels of serotonin were observed by TE treatment in all CDX and PDX tumors. Conclusion: In several CCA preclinical models, TE exhibited marked antitumor efficacy and it enhanced GemCis or NPT chemotherapy response. Hence, combination therapies with TE have the potential to improve clinical CCA therapy. Citation Format: Lily Darman, Margaret A. Schwarz, Roderich Schwarz, Niranjan Awasthi. Enhancing chemotherapy response by telotristat ethyl, an inhibitor of tryptophan hydroxylase involved in serotonin synthesis, in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 480.